Method for preparing tablet granulations



METHOD FOR PREPARING TABLET GRANULATIONS Filed April 26, 1957 :r Y I 7 ATTORNEY 2,877,159 .,.-Patented Mar. 10, .1959,

NIETHOD FOR PREPARING TABLET GRANULATIONS Leon Lachman, Summit, and William Lassell Suydam, Jr., Chatham, N. J., assignors to Ciba Pharmaceutical \lroducts, Inc., Summit, N. 1., a corporation of New ersey Application April 26, 1957, Serial No. 655,395 12 Claims. Cl. 167-82) This invention relates to an improvement in the art of preparing pharmaceutical tablet granulations.

The method presently employed for preparing tablet granulations in the pharmaceutical field involves a long series of steps which, because of the necessary multiple handling, are tedious and time consuming. With minor modifications this process generally includes weighing and mixing of the separate ingredients; wetting the mixed powdered ingredients with water, a hydroalcoholic solution, gum solution or paste; screening the moistened material to form granules; drying the granulation in ovens; screening the dry granulation to produce the proper size for compression; lubricating the granules so that they flow readily and do not stick to the punches upon compression and, finally, compressing the granulation into tablets.

In a general way, the above-described method represents the technique which is currently in use by the majority of pharmaceutical manufacturers. Because the preparation of tablets containing pharmaceutical ingredients is intended for human use, it is an extremely delicate and demandingly accurate operation. For this reason,

there has been some reluctance to adopt modifications which would speed up the over-all operation, it being the consensus that large scale production of pharmaceutical granulations must be accomplished by careful manual handling to insure accurate and optimal results.

, Although the process generally described above represents a satisfactory method for preparing pharmaceutical granulations, we have found that the disadvantage of multiple steps can be overcome in an eflicient manner, not .only without detracting in any Way from the over-all efliciency of the process, but additionally reducing the time period necessary for the preparation of granulations and substantially improving the character and physical properties of the granulation itself.

' We have found that within carefully controlled conditions of time and temperature it is possible to omit entirely not only one of the screening steps but also reducing substantially the time requirement for drying the granulation. According to our process, which we described in greater detail below, it is possible to moisten the powdered granulation mixture and convert it into suitable dried granules in a single operation, thus leaving only the requirement for one screening step and then direct compression. I

In a general way the process of this invention comprises the steps of treating adry, blended mixture of powders suitable for granulation with a granulating solution in vapor form and subjecting the resulting wetted mass to a vacuum.

To describe the invention in greater particularity, reference is made to the accompanying drawing which is an elevation with parts cut away and shown in section, showing suitable apparatus in which the process may be corrosion-resistant material which can withstand the ten perature and pressure of the process. The container is provided with heating means for example, a jacket 2 into which a heating fluid may be introduced through line 9 and withdrawn through line 10 by means of a rotary joint 8. The container is rotatably secured on either end by supports 13 and 14. Suitable power means for driving said container about its axis may be provided if so desired, although manual rotation may be employed.

In-the operation of the process, pre-weighed quantities, of powdered components are introduced into container 1. through the loading-unloading vacuum valve 15 which is then closed. While the powders are passing through a blending-mixing cycle, the granulating solution is heated in a jacketed vessel 3 into which a heating fluidmaylbe introduced through line 6 and withdrawn through line 7. During the blending cycle of the powdered mass in container 1 the valve 4 remains closed. At the conclusion of the blending cycle, and after the granulating solution in 3 has been heated sufficiently to be converted into the vapor phase, the valve 4 is opened to permit the vapor to pass through line 11 into the container 1. The filter 12 through which the vapor passes just prior to its escape into the container 1, may be made of material suitable for this purpose such as porous stainless steel. Although such porous end piece is preferred, it will be obvious to those skilled in the art that the line 11 may be so constructed that the aperture 12 may be fully opened, thus permittin the free escape of the vapor into container 1. v

After the escape of the vapor from container 3 through line 11 into the container 1 has been completed, the valve 4 is closed, the blending of the powdered mass with the recently introduced vapor in container 1 being continued to insure complete inter-mixing. When the vapor is fully incorporated with the powdered mass the valve 5 is opened causing a vacuum to pull on the container 1, removing all of the moisture therefrom and converting the moistened granulated mass into dry granules.

It will be noted that the process described above is one which is conducted under so-called atmospheric conditions, that is, the powdered material is moistened before the vacuum is applied. An alternative method, and one which is equally suitable for the purpose of this process isone conducted under so-called vacuum conditions! This modification of our process, which is intended to be included within the scope of the invention, may be described by referring to the drawing. In accordance with such modification the powdered components are subjected to a blending cycle in container 1, as previously described. When the cycle is complete both valves 4 and 5 are opened, thus placing the entire system under a vacuum. Valve 5 is then closed and heat is applied to container 3 through line 6 and to container 1 through line 9. After the vapor has been passed through line 11 into container 1 and a suitable time allowed for mixing, valve 5 is again opened to accomplish drying in the same manner as previously described above. This modification permits the operation of the process at considerably lowertemperatures thus permitting the vapor-vacuum granulation of pharmaceutical substances which are sensitive to treatment with heat.

A wide variety of solvents may beemployed inthe process of this invention, the only restriction upon th e character of solvent selected being that it should be readily convertible into a vapor phase. Those familiar with the practice of preparing pharmaceutical tablet granulations will know that solvents commonly employed for this purpose are water; hydroalcoholic mixtures, such as waterethanol; acetone; chloroform; ether and similar volatile liquids. I I p The most suitable granulating solution foru'se' in our process, and one which we prefer to employ, is a mix ture of water and from about 25% to about 75% ethanol. A solution of higher alcohol content for example from about to about 90%, may also be used but it is less frequently employed since such high alcoholic content is wasteful and unnecessary to the efiicient operation of the process.

Any suitable medium may be used for introduction into the jackets of containers 1 and 3 for the purpose of controlling, i. e., increasing or decreasing the temperatures thereof. The most convenient means is to introduce chilled, warm or hot water of suitable temperature into the jacket of container 1 through line 9 and hot water or steam into the jacket of container 3 through line 6. It will be noted, for reasons more fully described hereinbelow, that the temperature in container 3, since maxi mum efliciency of operation of the process depends to a large extent upon the control of the relative temperatures in the respective containers.

Inasmuch as it is one of the purposes of our process to introduce a vapor phase into container 1 without, at the same time, causing the decomposition of heat-sensitive pharmaceutical components, it will be apparent that although the temperature of container 3 must necessarily be relatively high in order to convert the granulating solution into a vapor phase, the temperature within container 1 must be sufliciently low to preclude decomposition caused by entry of the vapor.

Although the temperature used depend largely upon the particuar character and physical properties of the granulating solution and the powdered mass, we have found that a temperature differential from about 55 to about 75 degrees centigrade is suitable for the average granulation when using a hydroalcoholic solvent containing from about 25% to 75% alcohol. For example, if a 50% water-ethanol mixture is used as the granulating solution, the temperature in container 3 is maintained at approximately 100 degrees centigrade, and the temperature in container 1 is maintained at approximately 25 degrees to 45 degrees centigrade when preparing the granulation at atmospheric pressure.

To insure complete inter-mixing of the vapor phase with the powdered mass, it is advantageous to perform the introduction of the vapor into container 1 while the container is in motion about its axis. The rate of escape of the vapor phase from container 3 through line ,11 into container l depends largely upon the temperature differential between the two containers, the rate of flow of the vapor being directly proportional to the temperature difference. In other words, the greater the difierential,

the faster is the rate of flow of vapor.

Such differences in rates of flow, as reflected in differences in temperature, are caused by the creation of proportionately greater and lesser pressure differential between container 1 and container 3 which in turn causes the vapor in container 3 to be pulled over at a correspondingly greater or lesser rate.

Some care must be exercised in the rate at which the powders in container 1 are admixed with the vapor. If for example, the mixing is allowed to take place slowly, the moving powders will not adsorb the vapor rapidly enough, causing an accumulation of vapor condensate along the inside of'container 1. This, in turn, results in the adherence of semi-dry powder along the walls of the container. On the other hand, if the powdered mass is mixed too rapidly with the vapor, there will be an uneven distribution of vapor. with powder resulting in the formation of balls.

Although the size of container'l may be varied within wide limits depending upon the number of tablets it is desired to prepare in one operation, a suitable and convenient vessel is one approximately 16 cubic feet in volume, which will accommodate about 100 kilograms of powder. A container of such size may be revolved at ante of approximately 5 1025 'R. P.- M. during-the addi- 4 tion of the vapor phase, preferably at a rate of about 15 R. P. M. Larger and smaller vessels will require cor responding adjustments in revolution rates.

Although the novel process and its several modifications as described above embrace the broad concept of our invention-namely, the vapor wetting of blended pharmaceutical powders and vacuum drying of the wet granulation in a single continuous operation, it is to be understood that either of these improvements may be carried out independently of the other. Thus it may be desirable for purposes of economy or expediency, to pre pare the wet granulations by conventional means, that is by treating the dry, blended powders with the granulating solution in the form of a liquid and subjecting the resulting wet mass to drying under vacuum. This modification of our process may. be readily carried out with suitable, conventionally employed mixing equipment or, if desired, partially by manual handling. For example, the dry, powdered pharmaceutical ingredients are thoroughly'intermixed until a uniformly blended mixture is obtained. The dry mass is then treated with a granulating solution such as hydroalcoholic mixture of the type defined above until a wet granular mass of desired consistency" is obtained. The wet screened mass is then transferred to a suitable container, for example, such as that described in the accompanying drawing. The granulation is then subjected to drying under vacuum in the manner-described in detail hereinabove. The resulting dried granules'are screened and compressed into tablets.

It will be observed that the above-described modification of our process although not embracing the novel vapor-wetting step is nonetheless of considerable advantage in that it reduces the time required for drying the wet granules from about 24' hours to about 2 hours, one full day being normally required to dry a wet granular mass by the conventional oven method.

The alternative modification, that is to say, the employment of that step of the novel process which involves vapor-wetting of the dry, blended powder mixture may also be carried out independently of the vacuum-drying step if so desired. In such modification, the vapor-wetting is carried out in a suitable container such as that described in the accompanying drawing in the manner defined in detail hereinabove employing atmospheric conditions during the intermixture of the vapor phase with the dry powder. At the conclusion ofthe wetting step the wet granular mass'is discharged, screened, spread out on trays and placed in an ovenfor conventional drying. After the granules have dried, they are again screened to the desired size and then compressed into tablets;

It will be apparent to those skilled in the art that-the modification just described, although clearlypossible, would be the least desirable from a practical pointof view. The one single advantage of this modification over prior art processes resides in the considerable saving of granulating solution. Obviously when such solution is used in vapor form in a closed vessel, there is not only a minimum loss of liquid but more importantly a significantly improved distribution of granulating solution throughout the powder mass. This is essentially-dueto the fact that the granulating solution is added in a very finely dispersed state allowing for greater wetting properties. In fact, only a fraction of the volume is necessary when applied in vapor form as compared to the volume required when employed in liquid form in the'open air by hand. Conversely, once such vapor-wetting has been accomplished in a closed container, reversion to conventional drying methods would be impractical and inexpedient in View of the ease with which a vacuum could be directly applied to the wet mass to obtain dry granules suitable for screening and compression.

It is to be understood that the process of'this invention is broadly adaptable to the preparationof-a wide varietyof tablet granulationsin the: pharmaceutical field, and it is intended i that the broad .aswell .as ithflTSPfiCif-C features and modifications of our novel process be included within the scope of this application.

In the conventional tablet granulating process, the constituents, in addition to the active therapeutic component, are: an excipient or filler, such as lactose or sucrose; a lubricant such as magnesium stearate, calcium stearate, stearic acid, etc., and a binder such as tragacanth, acacia or a polyethylene glycol e. g. Carbowax 6000. These, as well as a wide variety of other substances Well known to those skilled in the art of preparing tablet granulations may be advantageously employed in the process of this invention.

Inasmuch as the new process may be readily controlled within very narrow limits of temperature and pressure, it is particularly suitable for the preparation of tablets containing pharmaceutical components which are sensitive to heat. Thus, it is possible to prepare, in accordance with our process, not only conventional tablets such as those containing acetylsalicylic acid, phenobarbital, phenacetin, antipyrine, benzedrine and similar therapeutics, but also tablets containing such labile pharmaceutical ingredients as vitamins, for example vitamin A, D, B etc.; alkaloids such as reserpine morphine, hyoscyamine, atropine, etc.; hormones such as cortisone, hydrocortisone, dehydrocortisone, dehydrohydrocortisone, etc., and antibiotics such as tetracycline, chlortetracycline, penicillin, streptomycin, etc.

What is claimed is:

1. The improvement in the art of preparing tablet granulations which comprises the step of treating a mixture of blended, pharmaceutical tableting ingredients with an organic vapor-phase granulating material.

2. The improvement in the art of preparing tablet granulations which comprises the step of treating a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder with an organic vapor-phase granulating material.

3. The improvement in the art of preparing tablet granulations which comprises the step of treating a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder with a hydroalcoholic vapor-phase granulation material.

4. The improvement in the art of preparing tablet granulations which comprises the step of treating a mixture of blended pharmaceutical tableting ingredients with a vapor-phase granulation material under atmospheric conditions and subjecting the resulting moistened granulation to a vacuum.

5. The improvement in the art of preparing tablet granulations which comprises the steps of treating a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder with a vapor-phase granulation material, under atmospheric conditions and subjecting the resulting moistened granulation to a vacuum.

6. The improvement in the art of preparing tablet granulations which comprises the steps of treating a mixture of a therapeutic ingredient, and excipient, a lubricant and a binder with a hydroalcoholic vapor-phase granulation material, under atmospheric conditions and subjecting the resulting moistened granulation to a vacuum.

7. The improvement in the art of preparing tablet granulations which comprises the step of treating a mixture of blended pharmaceutical tableting ingredients to a vacuum, treating the resulting mass with a vapor-phase granulation material and subjecting the moistened granulation to a vacuum.

8. The improvement in the art of preparing tablet granulations which comprises the steps of treating a mixture of a therapeutic ingredient, an excipient, a lu bricant and a binder to a vacuum, treating the resulting mass with a vapor-phase granulation material and subjecting the moistened granulation to a vacuum.

9. The improvement in the art of preparing tablet granulations which comprises the steps of subjecting a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder to a vacuum, treating the resulting mass with a hydroalcoholic vapor-phase granulation material, and subjecting the moistened granulation to a vacuum.

10. The improvement in the art of preparing tablet granulations which comprises the steps of subjecting a mixture of blended, pharmaceutical tableting ingredients to a vacuum and treating the resulting mass with a vaporphase granulation material.

11. The improvement in the art of preparing tablet granulations which comprises the steps of subjecting a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder to a vacuum and treating the resulting mass with a vapor-phase granulation material.

12. The improvement in the art of preparing tablet granulations which comprises the steps of subjecting a mixture of a therapeutic ingredient, an excipient, a lubricant and a binder to a vacuum and treating the resulting mass with a hydroalcoholic vapor-phase granulating material.

References Cited in the file of this patent UNITED STATES PATENTS 2,436,771 Hood Feb. 24, 1948 2,735,798 Kupferberg Feb. 21, 1956 FOREIGN PATENTS 527,302 Great Britain Oct. 7, 1940 OTHER REFERENCES Remingtons Practice of Pharmacy, The Mack Publ. Co., Easton, Pa., 1956, pp. 109, and 379.

Little et al.: Tablet Making, Northern Pub. Co., Liverpool England, 1949, page 34. 

1. THE IMPROVEMENT IN THE ART OF PREPARING TABLET GRANULATIONS WHICH COMPRISES THE STEP OF TREATING A MIX- 